Spinning Robots Mimic Cells to Unlock Immune Response Secrets

Scientists at the University of Chicago’s Pritzker School of Molecular Engineering and Department of Chemistry have created microscopic, rotating micro-robots that attach to immune cells and investigate their functionality.

The “hexapod,” or robot, offers researchers a novel and highly flexible approach to investigating immune cells that supports the development of immunotherapies for autoimmune, cancer, and infectious diseases.

Every hexapod robot has six arms filled with substances the immune system could identify as alien, like pieces of protein from a tumor, virus, or bacteria. Researchers can use the hexapods to scan vast arrays of immune cells, identifying which immune cells bind the target foreign molecules and how the hexapods' movements affect that binding.

Numerous aspects of which immune cells and how immune molecules sense pathogens remain uncharted territory, and now we have this new tool to help us understand the molecular interactions.

Jun Huang, Associate Professor and Study Author, Molecular Engineering, Pritzker School of Molecular Engineering

The study was published in Nature Methods.

Scientists often use biomaterials to study and manipulate the immune system, but we’ve developed a way to use inorganic materials, which is an incredibly unexplored area. The benefit of these materials is that we can change their properties in many more ways.

Bozhi Tian, Professor and Study Co-Senior Author, Department of Chemistry, Pritzker School of Molecular Engineering

A “T Cell” in a Haystack

White blood cells, called T cells, are in charge of identifying foreign pathogens that have been processed by dendritic cells, which are immune cells with long branching arms that catch pathogens and show fragments of the pathogens' molecules on their surface. A person’s body contains trillions of unique T cells, each with a distinctive T cell receptor that is expertly tuned to detect a pathogenic molecule (antigen) on a dendritic cell.

Researchers are often interested in learning which T cell can recognize a particular pathogen, aiming to enhance the immune system's ability to combat it. Searching through trillions of T cells for the precise match is like trying to find a needle in a haystack.

People have developed ways to do this, but they mostly rely on whether a T cell receptor binds an antigen. Since some T cell receptors can bind to an antigen without then provoking a strong immune response in the cell, we knew this wasn’t a perfect proxy.

Xiaodan Huang, Study Co-First Author, Pritzker School of Molecular Engineering

Previous T cell research platforms, which typically relied on isolated antigens that behaved differently from living dendritic cells, were likewise unable to replicate the importance of physical force in the interaction between dendritic cells and T cell receptors.

A Robotic Dendritic Cell

The scientists created a tiny robotic dendritic cell impersonator to get around these obstacles. The robot consists of six arms made of silicon dioxide, which is the main component of sand, to which antigens can be attached. Its central magnetic core rotates.

Tian and Huang’s lab groups tested the hexapod’s efficacy using known antigen-T cell receptor pairs. After applying antigen copies to each of the hexapod’s six legs, they submerged it in various T cell combinations. The hexapods bound only the correct cell, even when the matching T cell was present in small quantities among many other T cells.

Lingyuan Meng says, “We were incredibly happy with how well the system worked. The fact that it could pick out the right T cells with such a high accuracy exceeded our expectations.”

The research team also demonstrated their ability to examine the immune response that resulted from the T cells binding to the hexapod. For example, they could identify which of the two T cells bound to the hexapod more strongly, resulting in increased immune activity. The team additionally discovered that when the same T cells bound to static antigens, the immune responses were weaker than those triggered by the force of the spinning hexapod.

Huang says, “We’d now like to begin applying this to other antigens, including those from human cancers and pathogens. There are a lot of questions, both basic scientific questions and clinically relevant ones, that can be explored using these hexapods.”

The hexapods, for example, could be used to determine which T cells respond most strongly to which antigens.

Journal Reference:

Huang, X., et al. (2024) Multimodal probing of T cell recognition with hexapod heterostructures. Nature Methods. doi/10.1038/s41592-023-02165-7.